BI-2536

The concept of kinase-bromodomain dual targeted cancer therapeutics arose in recent years. Thus, the synergistic effects of the combination inhibition of bromodomain-containing protein 4 (BRD4) and polo-like kinase 1 (PLK1) attracted the researchers' attention for the great potential for cancer treatment. In this work, we designed and synthesized a series of small-molecule fluorescent probes targeting BRD4 and PLK1 based on our previous achievements on the study of BRD4 probes, aiming to construct a theragnostic system for cells and tissues. Among the probes, L1 exhibited a good binding affinity toward both PLK1 and BRD4 proteins, and its performances on target protein tracing in both cells and tissues as well were also impressive. By inhibiting PLK1 and BRD4, L1 took on obvious tumor cell suppressive activity that was similar to its pharmacophore BI-2536. Furthermore, the mechanism study revealed that dual inhibition of BRD4 and PLK1 modulated the key genes involving the cell cycle and apoptosis pathways, overcoming compensatory effects compared with the single-target inhibitors. Our work would provide a reliable toolkit for the development of PLK1/BRD4 dual-target inhibitors for cancer diagnostic and therapeutic agents, and bring out the ideas and cases for the design of visualization and therapy dual functional probes.